recent advances in granulation technologies

www.wjpps.com Vol 8, Issue 5, 2019.

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Chaudhari. World Journal of Pharmacy and Pharmaceutical Sciences

RECENT ADVANCES IN GRANULATION TECHNOLOGIES

Harshada S. Chaudhari*, Vidya P. Sable, Ujwala N. Mahajan

Department of Pharmaceutics, Dadasahheb Balpande College of Pharmacy, Besa, Nagpur.

ABSTRACT

The process of granulation is to transform fine powders into free-

flowing, dust-free granules that are easy to compress. During preparing

granules numerous challenges, we need to overcome due to a high-

quality requirement of the formed granules in terms of content

uniformity and physicochemical properties such as granule size, bulk

density, porosity, hardness, moisture, compressibility, etc. and also

together with physical and chemical stability of the drug. Granulation

process can be divided into two types: dry granulation that requires no

liquid and wet granulation that utilize a liquid in the form of

granulating fluids. The type of process selection requires a thorough

knowledge of physicochemical properties of the drug, excipients, required flow and release

properties. Conventionally, roller compaction and slugging are types of dry granulation. On

the other side, in wet granulation low shear mixing, high shear mixing, and fluid bed

granulation are present. As like any other scientific field, pharmaceutical granulation

technology also continues to change, and the arrival of the novel and innovative technologies.

Recent progress in the granulation techniques and technologies such as in dry granulations,

pneumatic dry granulation. In wet granulation wide range of innovations like reverse wet

granulation, steam granulation, moisture-activated dry granulation, thermal adhesion

granulation, freeze granulation, and foamed binder or foam granulation.

KEYWORDS: Granulation technologies, dry granulation, wet granulation.

INTRODUCTION

Granulation is a technique of particle enlargement by agglomeration, in which small fine or

coarse particles are converted into large agglomerates called granules. Granulation process is

one of the significant unit operations in the production of pharmaceutical dosage forms,

mostly tablets and capsules. In granulation technique, initial dry mixing of the necessary

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 8, Issue 5, 1467-1491 Review Article ISSN 2278 – 4357

Article Received on

19 March 2019,

Revised on 09 April 2019,

Accepted on 30 April 2019,

DOI: 10.20959/wjpps20195-13786

*Corresponding Author

Harshada S. Chaudhari

Department of

Pharmaceutics, Dadasahheb

Balpande College of

Pharmacy, Besa, Nagpur.


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powder ingredients along with the active pharmaceutical ingredient (API), so that a uniform

distribution of each ingredient throughout the powder mixture is achieved.[1]

Reasons for conducting granulation process

a. To enhance the API uniformity in the final product,

b. To increase the density of the blend so that it occupies less volume per unit weight for

better storage and shipment, to facilitate metering or volumetric dispensing,

c. To reduce dust during granulation process

d. To improve the appearance of the product and flow properties.

Ideal characteristics of granules include,

a. Spherical shape for improved flow,

b. Narrow particle size distribution for content uniformity and volumetric dispensing,

c. Sufficient fines to fill void spaces between granules for better compaction and

compression characteristics,

d. Adequate moisture and hardness to prevent breaking and dust formation during the

process.

The properties of the particles acquired after granulation depend on the particle size of the

drug and excipients, the type, concentration, and volume of binder and/or solvents, type of

granulator, granulation time, drying rate (temperature and time), etc. The primary methods by

which the agglomerated granules are formed include solid bridges, sintering, chemical

reaction, crystallization and deposition of colloidal particles.

The series of mechanisms by which granules are formed from the powder particles are

wetting and nucleation, coalescence or growth, consolidation, and attrition or breakage. The

blend of powders containing pharmaceutical excipients and API can be compressed into

tablets either by direct compression or after making granules by agglomeration or granulation

techniques. There are two types of granulation technique, dry granulation and wet

granulation, based on the type of method used to facilitate the agglomeration of powder

particles. Granulation technologies like roller compaction, spray drying, low/high shear

mixing, supercritical fluid, extrusion/ spheronization, fluid bed granulation, etc. have been

successfully used for the preparation of various pharmaceutical dosage forms. Pharmaceutical

granulation technology continues to change, and various improved, modified, and novel

techniques and technologies have been made available.[1-5]


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The changing description of granulation processes[3]

Quantitative prediction of granule attributes is difficult. In addition, the demarcation between

these mechanisms arbitrarily depends on the cut off size between granule and non-granular

material, which depends on the measurer’s interests and ability to count small particles.

These mechanisms could all be considered as cases of coalescence and/or breakage. It is

simply the size of the coalescing particles and the availability of surface liquid which varies

from case to case.

Fig 1: Granulation processes.

1. Wetting and nucleation, where the liquid binder is brought into contact with a dry powder

bed and is distributed through the bed to give a distribution of nuclei granules.

2. Consolidation and growth, where collisions between two granules, granules and feed

powder, or a granule and the equipment lead to granule compaction and growth.

3. Attrition and breakage, where wet or dried granules break up due to impact or

compaction in the granulator or during subsequent product handling.

Methods of granulation

Dry granulation technique uses mechanical compression (slugs) or compaction (roller

compaction) to facilitate the agglomeration of dry powder particles. Where the wet

granulation uses granulation liquid (binder/solvent) to facilitate the agglomeration by the

formation of wet mass by adhesion. Among these two techniques, wet granulation technique

involves multiple unit processes such as wet massing, drying, and screening, which are

complex, time-consuming, and expensive requiring large space and multiple equipments.


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The type of process selection requires a thorough knowledge of physicochemical properties

of the drug, excipients, required flow and release properties, etc.[1]

I. Recent progress in dry granulation

Pneumatic Dry Granulation (PDG)

II. Recent progress in wet granulation

Reverse Wet Granulation

Steam Granulation

Moisture-Activated Dry Granulation or Moist Granulation

Thermal Adhesion Granulation

Melt Granulation

Freeze Granulation

Foamed Binder or Foam Granulation[6-8]

I. Dry granulation Technique[9-28]

Dry granulation is a simple and low-cost method. This becoming more popular because of its

simplicity and cost efficiency. To improve dissolution, there are various methods like salt

formation, micronization, and addition of solvent or surface active agents. In a dry

granulation method, initially the primary powder particles are aggregated at high pressure.

There are two main processes,

1. Large tablet (known as a slug) is produced in a heavy duty tableting press (known as

slugging).

2. The powder is squeezed between two rollers to produce a sheet of material (roller

compaction).

This is a valuable alternative to direct compression, where the dose of a drug is too high or

too wet granulation when the drug is sensitive to heat, moisture or both. This method is also

used when other methods of granulation yield granules with a poor flow or compression

properties because there are fewer chances of segregation of drug and excipients. Long

processing time, relatively high capital investment on heavy-duty presses or compactors.

A. Slugging process

Slugging is the process of compressing dry powder of tablet formulation with the help of

tablet press having die cavity large enough in diameter to fill quickly. The accuracy or


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condition of a slug is not too important. Only sufficient pressure required to compact the

powder into uniform slugs should be used. Once slugs are produced they are reduced to

appropriate granule size for final compression by screening and milling.

B. Roller compaction[11, 16]

The compaction of powder by using pressure roll can also be accomplished by a machine

called chilsonator. Unlike tablet machine, the chilsonator turns out a compacted mass of

powder in a steady continuous flow. The powder is fed down between the rollers from the

hopper which contains a spiral auger to feed the powder into the compaction zone by which

density of powder enhanced. As like slugs, the aggregates are screened or milled for

production into granules.

Fig 2: Schematic diagram of dry granulation and two different techniques. Method I is

roller compaction and Method II is slugging.

Recent progress in dry granulation

Dry granulation achieved, either by roller compaction or by slugging. There has not been

much progress in the dry granulation technique, except for one important innovation known

as pneumatic dry granulation technology developed by Atacama Labs Oy (Helsinki, Finland).

Pneumatic Dry Granulation (PDG)

Pneumatic dry granulation (PDG), an innovative dry granulation technology, this technique

involved utilization of roller compaction together with a proprietary air classification method


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to prepare granules with the combination of compressibility and flowability. In this method,

granules are produced from powder particles by initially applying mild compaction force by

roller compactor to produce a compacted mass comprising a mixture of fine particles and

granules. The fine particles and/or smaller granules are separated from the intended size

granules in a fractioning chamber by use of gas stream (pneumatic system), whereas the

intended size granules are passed through the fractioning chamber to be compressed into

tablets. The fine particles and/or small granules are then transferred to a device such as a

cyclone and are either returned to the roller compactor for immediate reprocessing (recycling

or recirculation process) or placed in a container for reprocessing later to achieve the granules

of the desired size. This technique could successfully use to produce granules having good

flow property, for any formulations that produce compacts with a tensile strength of ~ 0.5

MPa.

Fig. 3: Schematic diagram of pneumatic dry granulation.

Merits of Pneumatic Dry Granulation

The faster speed of manufacturing compared with wet granulation.

Lower cost of manufacturing compared with wet granulation.

The system is closed offering safety advantages to the operators, due to low dust levels

and potential for sterile production or handling of toxic materials,

The end products are very stable - shelf life may be enhanced because of less moisture

content.

Little or no waste of material,

Scale-up is straightforward,


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The granules and tablets produced show fast disintegration properties, offering the

potential for fast release dosage forms, and Release time can be tailored to requirements.

II. Wet granulation Technique[29-38]

Wet granulation involves the preparing wet mass of dry primary powder particles using a

granulating fluid. The granulating fluid contains a solvent that must be volatile so that it can

be removed by drying for proper granulation. Granulating fluid includes water, ethanol, and

isopropanol either alone or in combination.

Merits of wet granulation

1. The cohesiveness and compressibility of powders are improved.

2. Good distribution and uniform content.

3. A wide variety of powders can be possessed together in a single batch.

4. Controlled release dosage form can be accomplished by the selection of a suitable binder

and solvent.

Demerits of wet granulation

1. Because of large number of processing steps, it requires a large area with temperature and

humidity.

2. It requires a number of pieces of expensive equipment also time consuming.

3. There is a possibility of material loss during processing due to transfer of materials from

one unit to another and have possibility of cross contamination.

Conventional wet granulation process involved low shear granulation, high shear granulation,

and fluid bed granulation.

A. Low shear granulation

It is the traditional method of making granules. Four types of equipment are mainly used in

this case.

1. Mixer machine to mix the ingredients.

2. Planetary mixer to make the wet mass.

3. Oscillating granulator to make the wet granules.

4. Dryer to dry the wet granules (Tray dryer or fluidized dryer).


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B. High shear mixture granulation

The high shear mixture has been widely used in Pharmaceutical industries for blending and

granulation. Blending and wet massing are accompanied by high mechanical agitation with

an impeller and a chopper. Mixing, densification, and agglomeration are achieved with the

help of shear and compaction force exerted by the impeller.

C. Fluid bed granulation

Fluidization is the operation by which fine solids are transformed into a fluid-like state

(dispersion) through contact with a gas. The fluid will support the particles at a certain gas

velocity, giving them free mobility without entrapment. Fluid bed granulation is a process by

which granules are prepared by spraying a binder solution onto a fluidized powder bed within

single equipment. The system involves the heating of air and then directing it through the

material to be processed for granulation. After that, the same air exit through the voids of the

product7. Fluid bed processing of pharmaceuticals was first reported by Wurster, and he used

air suspension technique to coat tablets, later used this technique in granulating and drying of

pharmaceuticals for the preparation of compressed tablets. Fluidized bed system contains

various components such as- Air handling unit (AHU), Spray Nozzle, Product container, and

air distribution, Disengagement area and process filters, Exhaust blower or Fan, Control

system and Solution delivery system.

Fig. 4: Fluid Bed granulation.

Recent progress in wet granulation

Wet granulation is the more popular technique, in which granules are produced by wet

massing of the excipients and API with granulation liquid with or without binder. Wet

granulation has various technical and technological innovations such as steam granulation,

moisture-activated dry granulation or moist granulation, thermal adhesion granulation, melt


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granulation, freeze granulation, foamed binder or foam granulation, and reverse wet

granulation.

1. Reverse wet granulation[39-41]

Reverse wet granulation process involving immersion of dry powder into the binder liquid,

thus eliminating the traditional granule nucleation process. The reverse-phase process

proceeds in such a way to reduced liquid saturation, thus decreasing the risk of uncontrolled

growth and batch loss. It improves the dissolution characteristics of poorly water-soluble

drugs by allowing uniform distribution of binder. The primary mechanism of the reverse-

phase granulation process was breakage of large moist agglomerates and mechanical

dispersion of the binder solution throughout the powder formulation. The size and porosity of

reverse-phase granules are controlled by the liquid saturation and impeller speed, with these

physical properties being best described by the dimensionless stokes deformation number and

the growth regime map.

Merits of Reverse Wet Granulation over Conventional Wet Granulation

This improves the dissolution characteristics of the poorly water-soluble drugs by

allowing uniform distribution of the binder and also improved flow properties of

powders.

This increases the chances of adequate and uniform contact between the drug and

hydrophilic polymer for better dissolution.

Uniform wetting and erosion of the granules.

The small and spherical-shaped granules with improved flow properties, uniform wetting

and erosion of the granules.

Use of currently available equipment such as high-speed mixer is another merit of this

technique. However, this technique produced granules with a greater mass mean diameter

and lower intragranular porosity when compared to the conventional wet granulation at

lower binder concentrations.


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Fig. 5: Reverse wet granulation.

2. Steam Granulation[42-45]

In steam granulation technique, steam is used as a binder instead of water or other granulating

fluids. A steam granulation technique involves the injection of a jet of steam into a bed of

fluidized particles of powder blend to be granulated. The jet of steam is substantially

enveloped by a jet of air to inhibit the premature condensation of the steam onto the fluidized

particles of powder blend and/or the condensation of the steam onto the neighboring walls of

an apparatus employed to fluidize the particles since this process inhibits excessive wetting

and lumping of the particles during their granulation.

Merits

Uniformly distributed in the powder particles.

Higher diffusion rate.

Results in more spherical granule formation.

No health hazards.

Maintain sterility.

Demerits

Requires special equipment for steam generation and transportation.

Requires high energy inputs.

Thermo labile materials are poor candidates.

More safety measure required.

Not suitable for all the binders.


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Fig. 6: Steam granulation.

3. Moisture-Activated Dry Granulation (MADG)[46-50]

In the moist granulation technique (MGT), a minimum amount of liquid is used to activate a

binder in a planetary mixer. Then, any excess moisture is absorbed by the addition of a

moisture-absorbing substance. Moist granulation yielded an increase in particle size

compared to direct compression method; these results are comparable to those from the

traditional wet granulation after drying and screening. The moist granulation technique

appears to have the potential for the development of controlled-release formulations.

In MADG, moisture is used to activate granule formation, there is no need to apply heat to

dry the granules. MADG is suitable for continuous processing. There are two main stages in

MADG: Agglomeration and Moisture distribution/ Absorption.

Benefits

This is applicable to more than 90% of the granulation need for pharmaceutical, food and

nutritional industry.

Time efficient and suitable for continuous processing.

Less energy involves during processing.

Drawbacks

Moisture sensitive and high moisture absorbing APIs are poor candidates.


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Fig. 7: Moisture-Activated Dry Granulation (MADG).

4. Thermal Adhesion Granulation (TAG)[51, 52]

Wei-Ming Pharmaceutical Company (Taipei, Taiwan) has developed this technique, and the

thermal adhesion granulation, analogous to moist granulation, utilizes the addition of a small

amount of granulation liquid and heat for agglomeration. It’s analogous to moist granulation

and utilizes the addition of a small amount of granulation liquid and heat for agglomeration.

This process uses both water and solvent as granulation fluids, also in this heat is used to

facilitate the granulation process. Drug & excipient mixture is heated to a temperature of 30-

130oC in a closed system under tumble rotation to facilitate the agglomeration of the powder

particle.

In this method of granulation, the drying process was eliminated, due to the addition of a low

amount of granulation liquid, which is mostly consumed by the powder particles during

agglomeration. Granules of the required particle size can be obtained by cooling and sieving.

It is applicable for preparing direct tableting formulations. This technique is quite simple and

convenient with low moisture and binder contents in a closed system for preparing highly

compressible materials or for modifying the poor characteristics of excipients. Besides, this

technique provides granules with better particle size, good flow properties and high tensile

strength that could be directly compressed into tablets with adequate hardness and low

friability.

The limitations of this technique are the requirement of considerably high energy inputs and

special equipment for heat generation and regulation. This technique is not suitable for all

binders and this is sensitive to thermolabile drugs.


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Fig. 8: Thermal Adhesion Granulation (TAG).

5. Melt granulation[53-62]

Melt granulation or thermoplastic granulation is a technique that facilitates the agglomeration

of powder particles using meltable binding agents, which melts or softens at relatively low

temperature (50-90°C). After cooling of the agglomerated powder and the consequent

solidification of the molten or soften binder complete the granulation process. Moreover,

Low melting binders can be added to the granulation process.

Addition of binders, either in the form of solid particles that melt during the process (melt-in

procedure or in situ melt granulation) or in the form of molten liquid. Optionally binder

containing the dispersed drug (spray-on or pump-on procedure), which displays a variety of

options to design final granular properties. Specifically, the melt-in procedure of melt

granulation process includes heating a mixture containing drug, binder and other excipients to

a temperature within or above the melting range of the binder.

Advantage

Time and cost-effective.

Controlling and modifying the release of drugs.

Water sensitive drugs are good candidates.

Disadvantage

Heat sensitive materials are poor candidates.

Lower melting point binder may melt or soften during handling or storage.


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Fig. 9: Melt granulation.

6. Freeze Granulation[63-70]

Freeze granulation technology, spray freezing, and subsequent freeze drying involves

spraying droplets of a suspension into liquid nitrogen followed by freeze-drying of the frozen

droplets. Powder suspension is sprayed into liquid nitrogen, by which drops are instantly

frozen into granules, and in the subsequent freeze-drying process. After that, the granules are

dried by sublimation of ice without any segregation effects. This process yields spherical as

well as free-flowing granules that could be formed by using both water based and solvent

based slurries. The great significance of this technology is that the structure and homogeneity

of the particles in the slurry or suspension are retained in the granules.

There are various kinds of material in dispersed form can be granulated using this

technology. This is suitable for the preparation of fine powder mixes with proper additives

for subsequent processing. This technology could be useful for the preparation of granules

that needs to formulate specific suspensions whose particle size and homogeneity need to be

preserved. Eventually, re-dispersible parenteral formulations, nanomaterials, solid self-

emulsifying drug delivery systems, etc. could benefit from this technology gives its ability to

maintain size and homogeneity.

The suspension quality always determines and reflects the quality of granule formed in terms

of homogeneity. In the pharmaceutical industry, the low-temperature and soft freeze-drying

have a vital advantage to minimize the damage of organic compounds and improve stability

and/or solubility. According to PowderPro AB, compared with spray drying, freeze


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granulation obviously produces protein particles with light and porous characteristics and

making powders with superior aerosol performance due to favorable aerodynamic properties.

Advantages

Freeze granulation technology, able to control the granule density through the solid

content of the suspension, preparation of granules with no cavities

The technique is useful for the preparation of granules that needs to be prepared from

suspensions whose particle size and homogeneity need to be preserved.

Improve stability and/or solubility because of minimizing the damage of organic

compounds.

High productivity yield due to low waste of material.

Recycling organic solvents will be possible.

Fig. 10: Freeze granulation.

7. Foam Granulation[71-90]

Foam granulation or foamed binder granulation technology, similar to spray agglomeration,

involves the addition of liquid/aqueous binder as foam instead of spraying or pouring liquid

onto the powder particles to be formulated. This foam binder technology was firstly

introduced by Dow Chemical Company (Midland, MI) in 2003 for delivering aqueous binder

systems in high shear and fluid bed wet granulation applications. To generate foam, foam

generator can be installed in the binder solution tank with high-shear granulator or fluid bed

granulator. Which helps to introduce the binder as foam rather than spraying or pouring in a

binder onto the moving powder particles. A simple foam generation by incorporating air into

a conventional water-soluble polymeric excipients binder such as METHOCEL.

Adding the binder solution as foam eliminates the problems of inconsistent and unpredictable

binder distribution that can affect tablet hardness and drug release. Compare to the sprayed


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water, the surface area and volume of the foamed binder/water are phenomenally high. Foam

granulation process, effectively improves the distribution of binder, even at a lower amount

of binder than that required in the conventional spray granulation method. Sprayed liquid

droplets have a low spread-to-soak ratio, which means they tend to soak into powders and

cause overwetting instate of spreading on the surface of the particles. This requiring high

levels of water and binder, and eventually drying to remove excess water.

On the other side, foamed binders have a high spread to-soak ratio, and because of this, the

binders are coated onto the particles rather than soaked, leading to less amount of binder and

more consistent binder distribution. These factors help to improve the reproducibility and

shorten the processing time. This process of granulation eliminates the spray nozzles and its

related processing variables and clogging problems.

Advantages

No spray nozzle is used.

Improve process robustness.

Less water required for granulation.

Time efficient drying.

Cost effective.

Uniform distribution of binder.

No over wetting.

Applicable for water sensitive formulation.

Fig. 11: Foam granulation.


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CONCLUSION

The pharmaceutical granulation techniques and technologies have improved over the years.

The research and development of new and efficient technologies by the interdisciplinary

scientists of pharmaceutical companies globally. Innovations with techniques and

technologies in granulation processes, which improves processability and quality of the

product formulations in addition to a substantial impact on the product development, time and

economy. During the formulation development, each drug substance poses a unique

challenge that must be taken into consideration at the process selection stage by the

formulation development scientists. The type of technique and technology selection requires


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thorough knowledge of physicochemical properties of the drug, excipients, required flow and

release properties, etc. because of each technique has its own merits and limitations. In the

pharmaceutical industry, although various technologies have been introduced from time to

time, only few have emerged as successful for real time utilization due to different kinds of

hurdles such as manufacturing efficiency, economy, regulatory issues, etc.

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